Acetylenes disubstituted with a furyl group and a substituted phenyl group having retinoid like activity

ABSTRACT

Retinoid like activity is exhibited by compounds of the formula ##STR1## where R 1  -R 3  independently are hydrogen, lower alkyl, cycloalkyl or lower alkenyl, A and B independently are hydrogen, lower alkyl, cycloalkyl, lower alkenyl, SR 4  or OR 4  where R 4  is lower alkyl, cycloalkyl or lower alkenyl; Y is selected from a group consisting of furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; E is lower alkenyl, lower alkynyl, lower cycloalkyl, lower branched chain alkyl, or is characterized by the formula (CH 2 ) n  where n is 0-5, and Z is H, OH, OR 5 , OCOR 5 , --COOH or a pharmaceutically acceptable salt, ester or amide thereof, --CH 2  OH, CH 2  OR 6 , CH 2  OCOR 6 , or --CHO, CH(OR 7 ) 2 , CHOR 8  O, or COR 9 , CR 9  (OR 7 ) 2 , CR 9  OR 8  O where R 5  is lower alkyl, phenyl or lower alkylphenyl, R 6  is lower alkyl, phenyl or lower alkylphenyl, R 7  is lower alkyl, R 8  is a divalent alkyl radical of 2-5 carbons, and R 9  is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a divisional of application Ser. No.07/669,696, filed on Mar. 14, 1991, to be issued as U.S. Pat. No.5,175,185, which in turn is a divisional of application Ser. No.07/458,963 filed on Dec. 29, 1989, issued as U.S. Pat. No. 5,013,744.

BACKGROUND

This invention relates to novel compounds having retinoid like activity.More specifically, the invention relates to compounds having asubstituted heteroaromatic portion and a substituted phenyl portion bothof which are linked to an ethynyl moiety.

RELATED ART

Carboxylic acid derivatives useful for inhibiting the degeneration ofcartilage of the general formula4-(2-(4,4-dimethyl-6-X)-2-methylvinyl)benzoic acid where X istetrahydroquinolinyl, chromanyl or thiochromanyl are disclosed inEuropean Patent Application 0133795 published Jan. 9, 1985. See alsoEuropean Patent Application 176034A published Apr. 2, 1986 wheretetrahydronaphthalene compounds having an ethynylbenzoic acid group aredisclosed, and U.S. Pat. No. 4,739,098 where three olefinic units fromthe acid-containing moiety of retinoic acid are replaced by anethynylphenyl functionality.

SUMMARY OF THE INVENTION

This invention covers compounds of Formula 1 ##STR2## wherein

R₁ -R₃ independently are hydrogen, lower alkyl, cycloalkyl or loweralkenyl, A and B independently are hydrogen, lower alkyl, cycloalkyl,lower alkenyl, SR₄ or OR₄ where R₄ is lower alkyl, cycloalkyl or loweralkenyl; Y is selected from a group consisting of furyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl or oxazolyl; E is lower alkenyl, loweralkynyl, lower cycloalkyl, lower branched chain alkyl, or ischaracterized by the formula (CH₂)_(n) where n is 0-5, and Z is H, OH,OR₅, OCOR₅, --COOH or a pharmaceutically acceptable salt, ester or amidethereof, --CH₂ OH, CH₂ OR₆, CH₂ OCOR₆, or --CHO, CH(OR₇)₂, CHOR₈ O, orCOR₉, CR₉ (OR₇)₂, CR₉ OR₈ O where R₅ is lower alkyl, phenyl or loweralkylphenyl, R₆ is lower alkyl, phenyl or lower alkylphenyl, R₇ is loweralkyl, R₈ is a divalent alkyl radical of 2-5 carbons, and R₉ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons.

In a second aspect, this invention relates to the use of the compoundsof Formula 1 for treating dermatoses, such as acne, Darier's disease,psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers.These compounds are also useful in the treatment of arthritic diseasesand other immunological disorders (e.g. lupus erythematosus), inpromoting wound healing, in treating dry eye syndrome and in delayingsun damage or reversing the effects of sun damage to skin. The compoundsare further useful for treating disorders of gut epithelialdifferentiation, such as ileitis colitis and Krohn's disease.

This invention also relates to a pharmaceutical formulation comprising acompound of Formula 1 in admixture with a pharmaceutically acceptableexcipient.

In another aspect, this invention relates to the process for making acompound of Formula 1 which process comprises reacting a compound ofFormula 2 with a compound of Formula 3 in the presence of cuprous iodideand Pd(PQ₃)₂ Cl₂ (Q is phenyl) or a similar complex ##STR3## where R₁-R₃ are the same as described above, X is a halogen, preferably iodine;A, B, E, and Y are the same as defined above; and Z is H, or an ester oran amide, or a protected or unprotected acid, alcohol, aldehyde orketone, giving the corresponding compound of Formula 1; or to theprocess of making a compound of Formula 1 which consists of reacting azinc salt of a compound shown in Formula 2 with a compound of Formula 3in the presence of Pd(PQ₃)₄ (Q is phenyl) or a similar complex.

In still another aspect, the present invention also relates topreparation of compounds of Formula 1 by conversion of compounds havingthe structure of Formula 4. ##STR4##

In Formula 4 the symbols A, B, R₁ -R₃, Y and E are defined as above inconnection with Formula 1, and Z' symbolizes such precursors of thegroup Z which can be readily converted by reactions well known toorganic chemists, into the desired Z group. Thus, the present inventionalso relates to the above-noted processes involving steps such as:

converting an acid of Formula 4 to a salt; or

forming an acid addition salt;

converting an acid of Formula 4 to an ester; or

converting an acid or ester of Formula 4 to an amide; or aldehyde; or

converting an alcohol of Formula 4 to an ether or ester; or

oxidizing an alcohol of Formula 4 to an aldehyde; or

converting an aldehyde of Formula 4 to an acetal; or

converting a ketone of Formula 4 to a ketal,

extending by homologation the length of the alkyl chain of a compound ofFormula 4.

GENERAL EMBODIMENTS Definitions

The term "ester" as used here refers to and covers any compound fallingwithin the definition of that term as classically used in organicchemistry. Where Z (of Formula 1) is --COOH, this term covers theproducts derived from treatment of this function with alcohols. Wherethe ester is derived from compounds where Z is --CH₂ OH, this termcovers compounds of the formula CH₂ OOCR₆ where R₆ is any substituted orunsubstituted aliphatic, aromatic or aliphatic-aromatic group.

Preferred esters are derived from the saturated aliphatic alcohols oracids of ten or fewer carbon atoms or the cyclic or saturated aliphaticcyclic alcohols and acids of 5 to 10 carbon atoms. Particularlypreferred aliphatic esters are those derived from lower alkyl acids oralcohols. Here, and where ever else used, lower alkyl means having 1-8carbon atoms and includes straight, branched chained and cycloalkylgroups as well. Also preferred are the phenyl or lower alkylphenylesters.

Amide has the meaning classically accorded that term in organicchemistry. In this instance it includes the unsubstituted amides and allaliphatic and aromatic mono-and di-substituted amides. Preferred amidesare the mono- and di-substituted amides derived from the saturatedaliphatic radicals of ten or fewer carbon atoms or the cyclic orsaturated aliphatic-cyclic radicals of 5 to 10 carbon atoms.Particularly preferred amides are those derived from lower alkyl amines.Also preferred are mono- and di-substituted amides derived from thephenyl or lower alkylphenyl amines. Unsubstituted amides are alsopreferred.

Acetals and ketals include the radicals of the formula --CK where K is(OR₇)₂. Here, R₇ is lower alkyl. Also, K may be --OR₈ O-- where R' islower alkyl of 2-5 carbon atoms, straight chain or branched.

A pharmaceutically acceptable salt may be prepared for any compound ofthis invention having a functionality capable of forming such salt, forexample an acid or an amine functionality. A pharmaceutically acceptablesalt may be any salt which retains the activity of the parent compoundand does not impart any deleterious or untoward effect on the subject towhich it is administered and in the context in which it is administered.

Such a salt may be derived from any organic or inorganic acid or base.The salt may be a mono or polyvalent ion. Of particular interest wherethe acid function is concerned are the inorganic ions, sodium,potassium, calcium, and magnesium. Organic amine salts may be made withamines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Where there is a nitrogensufficiently basic as to be capable of forming acid addition salts, suchmay be formed with any inorganic or organic acids or alkylating agentsuch as methyl iodide. Preferred salts are those formed with inorganicacids such as hydrochloric acid, sulfuric acid or phosphoric acid. Anyof a number of simple organic acids such as mono-, di- or tri-acid mayalso be used.

The preferred compounds of this invention are those where the ethynylgroup and the Z group are attached to the 2 and 5 positions respectivelyof a pyridine ring (the 6 and 3 positions in the nicotinic acidnomenclature being equivalent to the 2/5 designation in the pyridinenomenclature) or the 5 and 2 positions respectively of a thiophene grouprespectively; n is 0; and Z is --COOH, an alkali metal salt or organicamine salt, or a lower alkyl ester, or --CH₂ OH and the lower alkylesters and ethers thereof, or --CHO and acetal derivatives thereof. Themore preferred compounds shown in Formula 5 are:

ethyl 6-(3-tert butylphenyl)-ethynyl nicotinate (Compound 1, A=(CH₃)₃ C,B=H, R₁₀ =CH₂ --CH₃);

6-(3-tert butylphenyl)-ethynyl nicotinic acid (Compound 2, A=(CH₃)₃ C,B=H, R₁₀ =H;

ethyl 6-(4-tert butylphenyl)-ethynyl nicotinate (Compound 3, A=H,B=(CH₃)₃ C, R₁₀ =CH₂ --CH₃);

6-(4-tert butylphenyl)-ethynyl nicotinic acid (Compound 4, A=H, B=(CH₃)₃C, R₁₀ =H);

ethyl 6-[4-(4-methylpentyl)phenyl-ethynyl] nicotinate (Compound 5, A=H,B=(CH₃)₂ CH--(CH₂)₃, R₁₀ =CH₂ --CH₃), and

6-[4-(4-methylpentyl)phenyl-ethynyl] nicotinic acid (Compound 6, A=H,B=(CH₃)₂ CH--(CH₂)₃, R₁₀ =H.

Ethyl 6-[4-(1,1,4-trimethylpentyl)phenylethynyl]nicotinate. (Compound6a. A=H, B=(CH₃)₂ CH(CH₂)₂ C(CH₃)₂, R₁₀ =CH₂ CH₃

6-[4-(1,1,4-trimethylpentyl)phenylethynyl nicotinic acid (Compound 6b,A=H, B=(CH₃)₂ CH(CH₂)₂ C(CH₃)₂, R₁₀ =H

ethyl 6-(3-thio-tert-butoxyphenyl)-ethynyl nicotinate (Compound 7,A=(CH₃)₃ CS, B=H , R₁₀ =CH₂ --CH₃);

6-(3-thio-tert-butoxyphenyl)-ethynyl nicotinic acid (Compound 8,A=(CH₃)₃ CS, B=H, R₁₀ =H);

ethyl 6-(4-thio-tert-butoxyphenyl)-ethynyl nicotinate (Compound 9, A=H,B=(CH₃)₃ CS, R₁₀ =CH₂ --CH₃);

6-(4-thio-tert-butoxyphenyl)-ethynyl nicotinic acid (Compound 10, A=HB=(CH₃)₃ CS, R₁₀ =H);

ethyl 6-[4-(3-methyl-thio-2-butenoxyphenyl)]-ethynyl nicotinate(Compound 11, A=H, B=(CH₃)₂ C═CH--CH₂ --S--, R₁₀ =CH₂ --CH₃);

6-[4-(3-methyl-thio-2-butenoxyphenyl)]-ethynyl nicotinic acid (Compound12, A=H, B=(CH₃)₂ C═CH--CH₂ --S--, R₁₀ =H; ##STR5##

The compounds of this invention may be administered systemically ortopically, depending on such considerations as the condition to betreated, need for site-specific treatment, quantity of drug to beadministered, and similar considerations.

In the treatment of dermatoses, it will generally be preferred toadminister the drug topically, though in certain cases such as treatmentof severe cystic acne, oral formulation such as a solution, suspension,gel, ointment, or salve and the like may be used. Preparation of suchtopical formulations are well described in the art of pharmaceuticalformulations as exemplified, for example, Remington's PharmaceuticalScience, Edition 17, Mack Publishing Company, Easton, Pa. For topicalapplication, these compounds could also be administered as a powder orspray, particularly in aerosol form.

If the drug is to be administered systemically, it may be confected as apowder, pill, tablet or the like, or as a syrup or elixir for oraladministration. For intravenous or intraperitoneal administration, thecompound will be prepared as a solution or suspension capable of beingadministered by injection. In certain cases, it may be useful toformulate these compounds in suppository form or as an extended releaseformulation for deposit under the skin or intermuscular injection.

Other medicaments can be added to such topical formulation for suchsecondary purposes as treating skin dryness, providing protectionagainst light; other medications for treating dermatoses, preventinginfection, reducing irritation, inflammation and the like.

Treatment of dermatoses or any other indications known or discovered tobe susceptible to treatment by retinoic acid-like compounds will beeffected by administration of the therapeutically effective dose of oneor more compounds of the instant invention. A therapeutic concentrationwill be that concentration which effects reduction of the particularcondition, or retards its expansion. In certain instances, the drugpotentially could be used in a prophylactic manner to prevent onset of aparticular condition. A given therapeutic concentration will vary fromcondition to condition and in certain instances may vary with theseverity of the condition being treated and the patient's susceptibilityto treatment. Accordingly, a given therapeutic concentration will bebest determined at the time and place through routine experimentation.However, it is anticipated that in the treatment of, for example, acne,or other such dermatoses, that a formulation containing between 0.001and 5 percent by weight, preferably about 0.01 to 1% will usuallyconstitute a therapeutically effective concentration. If administeredsystemically, an amount between 0.01 and 100 mg per kg body weight perday, but preferably about 0.1 to 10 mg/kg, will effect a therapeuticresult in most instances.

The retionic acid like activity of these compounds was confirmed throughthe classic measure of retionic acid activity involving the effects ofretionic acid on ornithine decarboxylase. The original work on thecorrelation between retionic acid and decrease in cell proliferation wasdone by Verma & Boutwell, Cancer Research, 1977, 37, 2196-2201. Thatreference discloses that ornithine decarboxylase (ODC) activityincreased precedent to polyamine biosynthesis. It has been establishedelsewhere that increases in polyamine synthesis can be correlated orassociated with cellular proliferation. Thus, if ODC activity could beinhibited, cell hyperproliferation could be modulated. Although allcauses for ODC activity increase are unknown, it is known that12-O-tetradecanoyl-phorbol-13-acetate (TPA) induces ODC activity.Retionic acid inhibits this induction of ODC activity by TPA. Thecompounds of this invention also inhibit TPA induction of ODC asdemonstrated by an assay essentially following the procedure set out inCancer Res., 35: 1662-1670, 1975.

By way of example of retinoic acid-like activity it is noted that in theassay conducted essentially in accordance with the method of Verma &Boutwell, ibid, the following examples of the preferred compounds of thepresent invention (Compounds 1, 3, 5, 6a, 6b, 7, 9 and 11) attained an80% inhibition of TPA induced ODC activity at the followingconcentrations (IC₈₀)

    ______________________________________                                        Compound     IC.sub.80 conc (nmols)                                           ______________________________________                                        1            19.2                                                             3            11.5                                                             5            ˜300                                                        6a          95                                                                6b          47                                                               7            27.6                                                             9            36.2                                                             11           33.9                                                             ______________________________________                                    

SPECIFIC EMBODIMENTS

The compounds of this invention can be made by a number of differentsynthetic chemical pathways. To illustrate this invention, there is hereoutlined a series of steps which have been proven to provide thecompounds of Formula 1 when such synthesis is followed in fact and inspirit. The synthetic chemist will readily appreciate that theconditions set out here are specific embodiments which can begeneralized to any and all of the compounds represented by Formula 1.Furthermore, the synthetic chemist will readily appreciate that theherein described synthetic steps may be varied and or adjusted by thoseskilled in the art without departing from the scope and spirit of theinvention.

Referring now specifically to Reaction Scheme 1, the compounds of theinvention can be synthesized by coupling of a suitable substitutedphenylethyne compound (shown and defined in connection with Formula 2)with a suitable heterocyclic Compound (shown and defined in connectionwith Formula 3) which has a leaving group (X in Formula 3). In otherwords, the heteroaryl substituent is coupled to the substitutedphenylethyne compound (Formula 2) by reacting the latter with a halogensubstituted heteroaromatic compound (Formula 3) in which theheteroaramatic nucleus (Y) either has the desired substituent E-Z orwherein the actual substituent E-Z' can be readily converted to thedesired substituent by means of organic reactions well known in the art.##STR6##

Coupling of the substituted phenylethyne compound (Formula 2) with thereagent X-Y-E-Z (Formula 3) or with the reagent X-Y-E-Z' (where Z' isdefined as above in connection with Formula 4) is affected directly inthe presence of cuprous iodide, a suitable catalyst, typically of theformula Pd(PQ₃)₂ Cl₂ and an acid acceptor, such as triethylamine, byheating in a sealed tube under an inert gas (argon) atmosphere.

The resulting disubstituted acetylene compounds may be the targetcompound made in accordance with the invention (Formula 1), or maybecompounds described by Formula 4 which can be readily converted into thetarget compounds by such steps as salt formation, esterification,deesterification, homologation, amide formation and the like. Thesesteps are further discussed below

The disubstituted acetylene compounds of the invention (Formula 1) mayalso substituted phenylethyne compounds of Formula 2 into thecorresponding metal salts, such as a zinc salt (Compound 13) andthereafter coupling the salt 13 with the reagent X-Y-E-Z (Formula 3) orwith the reagent X-Y-E-Z' (Z' defined as above) in the presence of acatalyst having the formula Pd(PQ₃)₄ (Q is phenyl), or similar complex.

Derivatization of the compounds of Formula 1 (or of compounds of Formula4) is indicated in Reaction Scheme 1 as conversion to "Homologs andDerivatives" (Compounds 14).

More specifically with respect to either derivatization or deblocking ofprotected functionalities in compounds corresponding to Formula 1 orFormula 4, or with respect to the preparation of heteroaromaticcompounds of the formula X-Y-E-Z or of the formula X-Y-E-Z' (that isintermediates which after coupling either directly yield the compoundsof the invention, or yield the compounds of Formula 4) the following isnoted.

Where a protected heteroaromatic compound is needed to couple with thecompounds of Formula 2 such may be prepared from their correspondingacids, alcohols, ketones or aldehydes. These starting materials, theprotected acids, alcohols, aldehydes or ketones, are all available fromchemical manufacturers or can be prepared by published methods.Carboxylic acids are typically esterified by refluxing the acid in asolution of the appropriate alcohol in the presence of an acid catalystsuch as hydrogen chloride or thionyl chloride. Alternatively, thecarboxylic acid can be condensed with the appropriate alcohol in thepresence of dicyclohexylcarbodiimide and dimethylaminopyridine. Theester is recovered and purified by conventional means. Acetals andketals are readily made by the method described in March, "AdvancedOrganic Chemistry," 2nd Edition, McGraw-Hill Book Company, p 810).Alcohols, aldehydes and ketones all may be protected by formingrespectively, ethers and esters, acetals or ketals by known methods suchas those described in McOmie, Plenum Publishing Press, 1973 andProtecting Groups, Ed. Greene, John Wiley & Sons, 1981.

To increase the value of n before effecting a coupling reaction, wheresuch compounds are not available from a commercial source, theheteroaromatics where Z is --COOH are subjected to homologation bysuccessive treatment under Arndt-Eistert conditions or otherhomologation procedures. Alternatively, heteroaromatics where Z isdifferent from COOH, may also be homologated by appropriate procedures.The homologated acids can then be esterified by the general procedureoutlined in the preceding paragraph.

An alternative means for making compounds where n is 0-6 is to subjectthe compounds of Formula 1, where Z is an acid or other function, tohomologation, using the Arndt-Eistert method referred to above, or otherhomologation procedures.

The acids and salts derived from Formula 1 are readily obtainable fromthe corresponding esters. Basic saponification with an alkali metal basewill provide the acid. For example, an ester of Formula 1 may bedissolved in a polar solvent such as an alkanol, preferably under aninert atmosphere at room temperature, with about a three molar excess ofbase, for example, potassium hydroxide. The solution is stirred for anextended period of time, between 15 and 20 hours, cooled, acidified andthe hydrolysate recovered by conventional means.

The amide may be formed by any appropriate amidation means known in theart from the corresponding esters or carboxylic acids. One way toprepare such compounds is to convert an acid to an acid chloride andthen treat that compound with ammonium hydroxide or an appropriateamine. For example, the acid is treated with an alcoholic base solutionsuch as ethanolic KOH (in approximately a 10% molar excess) at roomtemperature for about 30 minutes. The solvent is removed and the residuetaken up in an organic solvent such as diethyl ether, treated with adialkyl formamide and then a 10-fold excess of oxalyl chloride. This isall effected at a moderately reduced temperature between about-10degrees and+10 degrees C. The last mentioned solution is then stirred atthe reduced temperature for 1-4 hours, preferably 2 hours. Solventremoval provides a residue which is taken up in an inert inorganicsolvent such as benzene, cooled to about 0 degrees C. and treated withconcentrated ammonium hydroxide. The resulting mixture is stirred at areduced temperature for

Alcohols are made by converting the corresponding acids to the acidchloride with thionyl chloride or other means (J. March, "AdvancedOrganic Chemistry", 2nd Edition, McGraw-Hill Book Company), thenreducing the acid chloride with sodium borohydride (March, Ibid, pg.1124), which gives the corresponding alcohols. Alternatively, esters maybe reduced with lithium aluminum hydride at reduced temperatures.Alkylating these alcohols with appropriate alkylhalides under Williamsonreaction conditions (March, Ibid, pg. 357) gives the correspondingethers. These alcohols can be converted to esters by reacting them withappropriate acids in the presence of acid catalysts ordicyclohexylcarbodiimide and dimethylaminopyridine.

Aldehydes can be prepared from the corresponding primary alcohols usingmild oxidizing agents such as pyridinium dichromate in methylenechloride (Corey, E. J., Schmidt, G., Tet. Lett., 399, 1979), or dimethylsulfoxide/oxalyl chloride in methylene chloride (Omura, K., Swern, D.,Tetrahedron, 1978, 34, 1651).

Ketones can be prepared from an appropriate aldehyde by treating thealdehyde with an alkyl Grignard reagent or similar reagent followed byoxidation.

Acetals or ketals can be prepared from the corresponding aldehyde orketone by the method described in March, Ibid, p 810.

Compounds where Z is H can be prepared from the correspondinghalo-heterocyclic entity, preferably where the halogen is iodine.

The intermediate substituted phenylethynes (compounds of Formula 2) canbe prepared from substituted phenyl compounds in accordance with thereactions described below.

Alkyl, cycloalkyl or alkenyl substituted phenylethynes (compounds shownin Formula 2 where R₁ -R₃ as well as A and B independently are hydrogen,lower alkyl, cycloalkyl, or lower alkenyl) can be synthesized inaccordance with Reaction Scheme 2, starting from a halogen (preferablybromo or iodo) substituted phenyl compound (Compound 15). Compound 15 isreacted with trimethylsilylacetylene Compound 16 in the presence ofcuprous iodide and a suitable catalyst, typically having the formulaPd(PQ₃)₂ Cl₂ (Q is phenyl). The reaction is typically conducted in thepresence of bis(triphenylphosphine) palladium (II) chloride catalyst, anacid acceptor, (such as triethylamine) under an inert gas (argon)atmosphere, by heating in a sealed tube. The resulting alkyl or alkenylsubstituted trimethylsilylethynylbenzene is shown as Compound 17 inReaction Scheme 2. ##STR7##

As is shown on Reaction Scheme 2, the trimethylsilyl moiety is removedfrom the trimethylsilylethynylbenzene 17 in the next synthetiic step, toprovide the alkyl or alkenyl substituted ethynylbenzene derivative(Compound 18). The latter reaction is conducted under basic conditions,preferably under an inert gas atmosphere.

Reaction Scheme 3 discloses a specific synthetic route to4-tert-butylphenyl ethyne (Compound 19) starting with 4-bromot-butylbenzene (Compound 20) which is either available commercially oris readily synthesized in accordance with known prior art. Thus, 4-bromot-butylbenzene 20 is heated with trimethylsilylacetylene 16 in thepresence of cuprous iodide, bis(triphenylphosphine) palladium (II)chloride catalyst, and triethylamine under an inert gas atmosphere. Theresulting trimethylsilyl-(4-tert-butyl)phenylethyne (Compound 21) isreacted with aqueous KOH in isopropanol to yield 4-tert-butylphenylethyne 19. ##STR8##

Reaction Scheme 4 discloses a specific synthetic route to3-tert-butylphenyl ethyne (Compound 22) starting with meta bromobenzoicacid (Compound 23), which is treated with trimethylaluminum in hexane toyield 3-tert-butyl bromobenzene (Compound 24). 3-Tert-butyl bromobenzene24 is thereafter converted into the ethyne derivative 22 through thetrimethylsilyl ethyne intermediate 25 in steps similar to the stepsdescribed in connection with Reaction Scheme 3.

Reaction Scheme 5 discloses a specific synthetic route to4-(4-methylpentyl)-phenylethyne (Compound 26). In accordance with thisscheme, bromobenzene (Compound 27) is reacted under Friedel Craftsconditions (AlCl₃) with the acid chloride (Compound 28) prepared in situfrom 4-methyl valeric acid, to yield 4-(1-oxo-4-methyl-pentyl)bromobenzene (Compound 29). Compound 29 is reduced under Wolff-Kishnerconditions (KOH, NH₂ NH₂) to yield 4-(4-methylpentyl) bromobenzene(Compound 30). The bromobenzene derivative 30 is converted to the ethynederivative 26 through the intermediate trimethylsilyl ethyne derivative31 in a manner similar to the conversion described in connection withReaction Scheme 3. ##STR9##

Reaction Scheme 6 discloses specific synthetic steps leading to4-(1,1,4-trimethylpentyl)phenylethyne (Compound 32). In this syntheticroute 4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 29, obtained asshown in Reaction Scheme 5) is reacted under a nitrogen atmosphere withtrimethylaluminum in hexane to yield4-(1,1,4-trimethylpentyl)bromobenzene (Compound 33). The bromobenzenederivative 33 is converted through the correspondingtrimethylsilylethyne derivative 34 into the target intermediate 32 bytreatment with trimethylsilyl ethyne and subsequently with KOH inisopropanol, as described above. ##STR10##

Specific examples of coupling the above-noted phelylethynes withreagents of the General Formula 3 are disclosed below under the heading"Specific Examples".

Alkylthio, alkyloxy, cycloalkylthio, cycloalkyloxy, alkenylthio, andalkenyloxy substituted phenylethynes which may or may not beadditionally substituted with alkyl, cycloalkyl or alkenyl groups, inother words, compounds shown in Formula 2 where R₁ -R₃ independently arehydrogen, lower alkyl, cycloalkyl, or lower alkenyl and where at leastone of A and B is alkylthio, alkyloxy, cycloalkylthio, cycloalkyloxy,alkenylthio, or alkenyloxy, can be synthesized in accordance with thesteps outlined in Reaction scheme 7.

Thus, in accordance with Reaction Scheme 7 a halogen substituted phenol,preferably an iodopheol or a bromophenol, or a corresponding thiophenol(Compound 35) which may or may not be additionally substituted with analkyl, alkenyl or cycloalkyl group (in Compound 35 X' is halogen, Y' issulphur or oxygen and R₁ -R₃ are defined as in connection withFormula 1) is alkylated with a reagent R₄ -X where X" is a leaving groupsuch as a halogen, and R₄ is defined as in connection with Formula 1.Alternatively, the R₄ group can also be formed by reacting the halogensubstituted thiophenol or phenol (Compound 35) with an appropriatealkene. The resulting alkoxy, thio-alkoxy , alkenoxy or thio-alkenoxyhalobenzene (Compound 36) is reacted with trimethylsilylacetylene(Compound 16) in the presence of cuprous iodide and a suitable catalyst,such as Pd(PQ₃)₂ Cl₂, where Q is phenyl. As is noted in connection withthe analogous reaction disclosed in Reaction Scheme 2, the reaction istypically conducted in the presence of bis(triphenylphosphine)palladium(II) chloride catalyst, and an acid acceptor, such as triethylamine,under an inert gas (argon) atmosphere. The resulting alkoxy,thio-alkoxy, alkenyloxy or thio-alkenyloxy trimethylsilylethynylbenzenederrivatives are shown as Compound 37 in Reaction Scheme 7. ##STR11##

The trimethylsilyl moiety is removed from thetrimethylsilylethynylbenzene 37 in the next synthetic step, to providethe alkoxy, thio-alkoxy, alkenoxy or thio-alkenoxy substitutedethynylbenzene derivative (Compound 38). ##STR12##

Reaction Scheme 8 discloses a specific series of synthetic steps whichlead to 4-thio-tert-butoxyphenyl ethyne (Compound 39). Thus,4-bromo-thiophenol (Compound 40) is reacted with isobutylene gas toyield 4-bromophenyl-tert-butyl-sulfide (Compound 41). Compound 41 isthereafter reacted under the conditions described above, withtrimethylsilylacetylene (Compound 16) and the resulting trimethylsilylphenylethyne derivative 42 is thereafter hydrolyzed to yield Compound39. The corresponding 3-thio-tert-butoxyphenyl ethyne (Compound 43) canbe synthesized from 3-bromo-thiophenol under substantially similarconditions. ##STR13##

Reaction Scheme 9 discloses synthetic steps which lead to4-(3-methyl-thio-2-butenoxy)phenyl ethyne (Compound 44).4-Bromo-thiophenol (Compound 40) is heated with4-bromo-2-methyl-2-butene (Compound 45) in a suitable solvent (such asacetone) in the presence of strong base (NaOH) to yield4-bromophenyl-3-methyl-2-butenyl-sulfide (Compound 46). Compound 46 isconverted to the ethyne derivative 44 through the trimethylsilyl ethynecompound 47 by the reactions which are described above. ##STR14##

Reaction Scheme 10 illustrates specific synthetic steps which can beutilized to obtain 4-(3-methyl-thiobutoxy)-phenyl ethyne (Compound 48).In this synthetic procedure 4-bromothiophenol (Compound 40) is heatedwith 1-bromo-3-methyl-2-butane (Compond 49) in a suitable solvent in thepresence of strong base (refluxing acetone and NaOH) to yield4-bromophenyl-3-methylbutyl-sulfide (Compound 50). Compound 50 istransformed to the desired ethyne derivative 48 through the intermediatetrimethylsilylethyne 51. ##STR15##

An alternative general route for introducing the ethyne (acetylenic)function into a phenyl or substituted phenyl derivative so as to obtainthe intermediates of Formula 2, is disclosed in Reaction Scheme 11. Inaccordance with this general procedure, a suitably substituted benzenederivative (Compound 52) is acetylated under Friedel Crafts conditionsto provide the acetophenone derivative 53. The acetylation is preferablyconducted in the presence of AlCl₃ and in nitromethane solvent. Theacetylenic (triple) bond is introduced into the molecule by convertingthe acetyl moiety of the acetophenone derivative 53 to an acetylenemoiety. This is accomplished, preferably, by treatment with lithiumdiisopropylamide (at low temperature, such as-78 degrees C.) whichcauses enolization of the acetyl group. The intermediate enol compound(not shown in Reaction Scheme 11) is esterified by treatment withdiethylchlorophosphate (or the like) and is again reacted at reducedtemperature (e.g.-78 degrees C.) with two equivalents of lithiumdiisopropylamide, to form the triple bond (presumably by an eliminationreaction) and to yield the compounds of Formula 2.

It is noted at this point that the present invention is not intended tobe limited or bound by the above-mentioned and other theories ofreaction mechanisms. Brief description of the theories of reactionmechanism of the above-noted reaction is given to further enable andfacilitate the work of a skilled artisan in the field to modify andadjust the synthetic conditions to fit particular specific intermediatesand to make the several compounds of the invention, without departingfrom the scope and spirit of the invention.

The following examples of specific compounds of the invention, andspecific examples of the synthetic steps in which the compounds andcertain intermediates are made, are set out to illustrate the invention,not to limit its scope.

SPECIFIC EXAMPLES Ethyl 6-chloronicotinate (Compound 54)

A mixture of 15.75 g (0.1 mol) 6-chloronicotinic acid, 6.9 g (0.15 mol)ethanol, 22.7 g (0.11 mol) dicyclohexylcarbodiimide and 3.7 gdimethylaminopyridine in 200 ml methylene chloride was heated at refluxfor 2 hours. The mixture was allowed to cool, solvent removed in vacuoand residue subjected to flash chromatography to give the title compoundas a low-melting white solid. PMR (CDCl₃): & 1.44 (3H, t, J˜6.2 Hz) 4.44(2H, q, J˜4.4 Hz), 7.44 (1H, d, J˜8.1 Hz), 8.27 (1H, dd, J˜8.1 Hz, 3Hz), 9.02 (1H, d, J˜3 Hz).

The foregoing procedure may be used to esterify any of the otherhalo-substituted acids employed in the making of compounds of theinvention, such as:

ethyl 2-(2-chloropyrid-5-yl)acetate;

ethyl 5-(2-chloropyrid-5-yl)pentanoate;

ethyl 2-(2-iodofur-5-yl)acetate;

ethyl 5-(2-iodofur-5-yl)pentanoate;

ethyl 2-(2-iodothien-5-yl)acetate;

ethyl 5-(2-iodothien-5-yl)pentanoate;

ethyl 2-(3-chloropyridazin-6-yl)acetate;

ethyl 5-(3-chloropyridazin-6-yl)pentanoate; and the correspondingchloro, or other halo, substituted pyrimidinyl or pyrazinyl analogues ofsuch esters. The just mentioned esters (includingethyl-6-chloronicotinate, Compound 54) can serve as the reagents,X-Y-E-Z for coupling with the correspoding ethynyl compounds (such asCompounds 19, 22, 26, 32, 39, 44, and 48, or their zinc salts) toprovide the target compounds of the invention.

3-Tert-butyl bromobenzene (Compound 24)

A suspension of 4.02 g (20 mmol) of m-bromobenzoic acid (Compound 23) in10 ml hexane Was cooled in an ice-bath under nitrogen and then treatedslowly With 40 ml of 2 M (80 mmol) trimethylaluminum in hexane. Thehexane was removed by distillation under nitrogen and the apparatusmodified for reflux. The reaction mixture was then heated in an oil bathat 140-150 degrees C. for 3 hours. The oil bath was then replaced by anice-water bath and the reaction mixture was quenched by the slowdropwise addition of water. The mixture was acidified with dilute HCland mixture heated at reflux until the aluminum salts were dissolved.The reaction mixture was allowed to cool and extracted with 3×8 mlether. The ether extracts were combined, washed with dil. HCl, water andsaturated NaCl and then dried (MGSO₄). The solvent was removed in-vacuoand the residue distilled to give a mixture of the title compound and3-(1-methyl-ethenyl) bromobenzene as a colorless oil. A small portion(200 mg) of this mixture was dissolved in 1 ml of methylene chloride andthen treated with a solution of 200 mg of m-chloroperbenzoic acid in 4ml of methylene chloride. The mixture was stirred at room temperaturefor 1 hour and the methylene chloride removed in-vacuo. The residue wasdissolved in hexane and filtered through a short silica column and thefiltrate concentrated in-vacuo to give pure title compound as acolorless oil. PMR (CDCl₃) & 1.30 (9H, s), 7.25 (1H, m), 7.41 (2H, m),7.65 (H, t, J˜2.1 Hz).

4-(1-oxo-4-methyl-pentyl) bromobenzene (Compound 29)

A mixture of 25 g (.215 mol) of 4-methyl valeric acid and 9.35 g (0.247mol) of thionyl chloride was heated at reflux for 1.5 hour. The excessthionyl chloride was removed under reduced pressure using a cryogenictrap. The residue was taken up with 120 g (0.764 mol) of bromobenzene(Compound 27) and the mixture was cooled in an ice-bath and then treatedwith 23 g (0.172 mol) of anhydrous aluminum chloride through a powderaddition funnel The mixture was stirred at room temperature for 82 h andthen quenched by the addition of 50 ml of an ice/water mixture, followedby 30 ml of conc. HCl. The organic layer was separated and the aqueouslayer extracted with 2×50 ml of ether. The organic extracts werecombined and washed successively with water and saturated NaCl solutionand then dried (MGSO₄) The solvent was then removed in-vacuo and theresidue purified by distillation (˜80 degrees C./0.01 mm) to give thetitle compound as a colorless solid. PMR (CDCl₃): & 0.94 (6 H, d, J˜6.0Hz), 1.53-1.68 (3H, m), 2.85-2.97 (2H, m)., 7.60 (2H, d, J˜8.4 Hz), 7.83(2H, d, J˜8.4 Hz).

4-(4-methylpentyl) bromobenzene (Compound 30)

A mixture of 6.45 g (115 mmol) of potassium hydroxide and 42 ml oftriethylene glycol was heated at around 100 degrees C. until thepotassium hydroxide was dissolved. The mixture was allowed to cool andthen treated with 10 g (39mmol) of 4-(1-oxo-4-methylpentyl) bromobenzene(Compound 29) followed by 3 g (94 mmol) of hydrazine hydrate. Themixture was slowly brought to reflux and heated at reflux for 1 hour.The apparatus was modified for distillation and the mixture heated untilapproximately 7 ml of liquid had distilled over and the flasktemperature had reached 220 degrees C. The apparatus was again modifiedfor reflux and the mixture was heated at reflux for 5 hours and thenstirred at room temperature for 8.5 hours. The mixture was then heatedto 100 degrees C. and poured into 40 ml of water and the flask rinsedwith an additional 25 ml of water. This diluted mixture was acidified topH=2 with conc. HCl and extracted with ether. The ether extract waswashed successively with water and saturated NaCl and then dried(MGSO₄). The solvent was removed in vacuo and the residue subjected tokugelrohr distillation (70 degrees C., 0.05 mm) to give the titlecompound as a colorless oil. PMR (CDCl₃) : & 0.88 (6H, d, J˜6 Hz),1.12-1.26 (2H, m), 1.48-1.66 (3H, m), 2.54 (2H, t, J˜7.7 Hz) 7.06 (2H,d, J˜8.3 Hz), 7.39 (2H, d, J˜8.3 Hz).

4-(1,1,4-Trimethyl-pentyl) bromobenzene (Compound 33)

To a cooled (ice bath) solution of 5.35 g (20.9 mmol) of4-(1-oxo-4-methylpentyl) bromobenzene (Compound 29) and 200 ml of waterin 8 ml of chlorobenzene was added slowly, under nitrogen, 20.9 ml of 2M(41.8 mmol) trimethylaluminum in hexane. The hexane was removed bydistillation under nitrogen and the residue heated at reflux for 80hours. The reaction mixture was then cooled in an ice bath and quenchedby the slow addition of water. The mixture was then treated with 24 mlof 2N HCl and heated until the aluminum salts were dissolved. Themixture was cooled and extracted with 3×20 ml of ether. The etherextracts were combined and washed successively with water and saturatedNaCl and then dried (MGSO₄). The solvent was removed in-vacuo and theresidue distilled (90-100 degrees C./0.16 mm) to give a crude productwhich appeared to be a mixture of the desired title compound, startingbromoketone and some olefinic material. This product was then dissolvedin 20 ml of methylene chloride, treated with 2 g of m-chloroperbenzoicacid and stirred at room temperature for 12 hours. The solvent was thenremoved in-vacuo and the residue purified by flash chromatography(silica, hexane) to give the title compound as a colorless oil PMR(CDCl₃): & 0.82 (6H, d, J˜6.9 Hz), 0.85-0.97 (2H, m), 1.27 (6H, s),1.32-1.49 (1H, m), 1.53-1.62 (2H, m), 7.20 (2H, d, J˜8.7 Hz), 7.42 (2H,d, J˜8.7 Hz).

Trimethylsilyl (4-tert-butyl) phenylethyne (Compound 21)

A stirred mixture of 3.05 g (14. 31 mmol) of 4-tert-butyl-bromobenzene(Compound 20), 1.41 g (14.39 mmol) of trimethylsilylacetylene (Compound16), 139 mg (0.13 mmol) of cuprous iodide, 293 mg (0.42 mmol) ofbis(triphenyophosphine) palladium (II) chloride and 3 ml oftriethylamine was flushed with nitrogen and then heated under nitrogenat 65-70 degrees C. for 20 hours. The reaction mixture was stirred atroom temperature for a further 4 hours and the triethylamine thenremoved under vacuum. The residue was purified by flash chromatography(silica; hexanes) to give the title compound as a colorless oil. PMR(CDCl₃): & 0.26 (9H, s), 1.31 (9H, s), 7.32 (2H, d, J˜8.2 Hz), 7.42 (2H,d, J˜8.2 HZ).

Trimethylsilyl (3-tert-butyl) phenylethyne (Compound 25)

Using the same general procedure as described for Compound 21, but using3-tert-butyl-bromobenzene, (Compound 24) the title compound wassynthesized as a colorless oil. PMR (CDCl₃): & 0.36 (9H, s), 1.40 (9H,s), 7.32 (1H, m), 7.37-7.47 (2H, m), 7.61 (1H, m).

Trimethylsilyl 4-(4-methylpentyl)] phenylethyne (Compound 31)

Using the same general procedure as described for Compound 21, but usinginstead 4-(4-methylpentyl) bromobenzene (Compound 30), the titlecompound was synthesized as a colorless oil. PMR (CDCl₃): & 0.32 (9H,s), 0.93 (6H, d, J˜6.6 Hz), 1.18-1.29 (2H, m), 1.52-1.70 (3H, m), 2.58(2H, t, J˜7.7 Hz), 7.12 (2H, d, J˜8.1 Hz), 7.43 (2H, d, J˜8.1 Hz).

Trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 34)

Using the same general procedure as described for Compound 21, but usinginstead 4-(1,1,4-trimethylpentyl) bromobenzene (Compound 33), the titlecompound was synthesized as a colorless oil. PMR (CDCl₃): & 0.26 (9H,s), 0.81 (6H, d, J˜6.6 Hz), 0.85-0.97 (2H, m), 1.29 (6H, s), 1.33-1.46(1H), 1.54-2.65 (2H, m), 7.27 (2H, d, J˜8.1 Hz), 7.42 (2H, d, J˜8.1 Hz).

(4-tert-butyl) phenylethyne (Compound 19)

To a stirred solution of 1.44 g (6.23 mmol) of trimethylsilyl(4-tert-butyl) phenylethyne (Compound 21) in 5 ml of isopropanol wasadded 10 ml of 1N aqueous KOH and the mixture then stirred at roomtemperature for 6.5 hours. The isopropanol was removed under vacuum andthe residue extracted with ether. The ether extract was washed withdilute HCl until the washings were acidic. The ether solution was thensuccessively washed with water, saturated NaCl and NaHCO₃ solutions andthen dried (MGSO₄). Solvent was then removed in-vacuo to give the titlecompound as a colorless oil. PMR (CDCl₃): & 1.34 (9H, s), 3.05 (1H, s),7.37 (2H, d, J˜8.2 Hz), 7.46 (2H, d, J˜8.2 Hz).

(3-tert-butyl) phenylethyne (Compound 22)

Using the same general procedure as described for Compound 19), butusing instead trimethylsilyl (3-tert-butyl) phenylethyne (Compound 25)and aqueous KOH in methanol, the title compound was synthesized as acolorless oil. PMR (CDCl₃): & 1.29 (9H s) 3.03 (1H s), 7.22 (1H, t J˜7.5Hz), 7.30 (1H, dt, J˜7.5 Hz, 1.5 Hz), 7.36 (1H, dt, J˜7.5 Hz, 1.5Hz),7.53 (1H, t, J˜1.5 Hz).

[4-(4-methylpentyl)] phenylethyne (Compound 26)

Using the same general procedure as described for Compound 19), butusing instead trimethylsilyl [4-(4-methylpentyl)] phenylethyne (Compound31), the title compound was synthesized as a colorless oil. PMR (CDCl₃):& 0.94 (6H, d, J˜6.6 Hz), 1.20-1.32 (2H, m), 1.56-1.62 (3H, m), 2.64(2H, t, J˜7.8 Hz), 3.08 (1H, s), 7.18 (2H, d, J˜8.1 Hz), 7.47 (2H, d,J˜8.1 Hz).

[4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 32)

Using the same general procedure as described for Compound 19, but usinginstead trimethylsilyl [4-(1,1,4-trimethylpentyl)] phenylethyne(Compound 34), the title compound was synthesized as a colorless oil.PMR (CDCl₃): & 0.81 (6H, d, J˜6.6 Hz), 0.85-0.96 (2H, m), 1.29 (6H, s),1.32-1.48 (1H, m). 1.55-1.66 (2H, m)., 3.04 (1H, s), 7.29 (2H, d, J˜8.4Hz), 7.44 (2H, d, J˜8.4 Hz).

Ethyl-6-(4-tert-butylphenylethynyl) nicotinate (Compound 3)

A mixture of 477.7 mg (3.02 mmol) of 4-tert-butylphenylethyne (Compound19), 556.5 mg (3.01 mmol) of ethyl-6-chloronicotinate (Compound 54),27.8 mg (0.15 mmol) of cuprous iodide, 58.7 mg (0.08 mmol) ofbis(triphenylphosphine palladium (II) chloride and 2 ml of triethylaminewas degassed under nitrogen and then stirred under nitrogen at roomtemperature for 40 hours. The mixture was then heated at 65 degrees C.for 12 hours, cooled to room temperature and the excess triethylamineremoved under vacuum. The residue was taken up in water and extractedwith ether. The solvent was then removed in-vacuo and the residuepurified by flash chromatography (silica 5% ethyl acetate in hexane) togive the title compound as a pale brown solid. PMR (CDCl₃) : & 1.33 (9H,s), 1.42 (3H, t, J˜7.1 Hz); 4.42 (2H, q, J˜7.1 Hz), 7.40 (2H, d, J˜8.4Hz), 7.53-7.61 (3H, m), 8.28 (1H, dd, J˜8.1 Hz, 2.0 Hz), 9.20 (1H, d,J˜2.0 Hz).

Ethyl-6-(3-tert-butylphenylethynyl) nicotinate (Compound 1)

Using the same general procedure as described for Compound 3, but usinginstead 3-tert-butylphenylethyne (Compound 19), the title compound wassynthesized as a white solid. PMR (CDCl₃): & 1.34 (9H, s), 1.42 (3H, t,J˜7.2 Hz), 4.43 (2H, q, J˜7.2 Hz), 7.28-7.36 (1H, m), 7.40-7.46 (2H, m),7.60 (1H, d, J˜8.1 Hz), 7.67 (1H, s), 8.29 (1H, dd, J˜8.1 Hz, 2.1 Hz),9.21 (1H, d, J˜2.1 Hz).

Ethyl-6-[4-(4-methylpentyl) phenylethynyl] nicotinate (Compound 5)

Using the same general procedure as described for Compound 3, but usinginstead 4-(4-methylpentyl) phenylethyne (Compound 26), the titlecompound was synthesized as a yellow solid. PMR (CDCl₃): & 0.91 (6 H, d,J˜6.6 Hz), 1.20-1.30

(1H, m)., 1.47 (3H, t, J˜7.2 Hz), 1.51-1.72 (3H, m), 2.63 (2H, t, J˜7.8Hz), 4.45 (2H, q, J˜7.2 Hz), 7.22 (2H, d, J˜8.4 Hz), 7.53-7.64 (3H, m),8.30 (1H, dd, J˜8.1 Hz, 2.1 Hz), 9.23 (1H, d, J˜2.1 Hz).

Ethyl 6-[4-(1,1,4-trimethylpentyl) phenylethynyl] nicotinate (Compound6a)

Using the same general procedure as described for Compound 3, but usinginstead [4-(1,1,4-trimethylpentyl)] phenylethyne (Compound 32), thetitle compound was synthesized as a yellow oil. PMR (CDCl₃): & 0.83 (6H,d, J˜6.7 Hz), 0.88-0.99 (2H, m), 1.32 (6H, s), 1.35-1.50 (4H, m),1.59-1.70 (2H, m), 4.45 (2H, q, J˜7.1 Hz), 7.36 (2H, d, J˜8.4 Hz),7.55-7.64 (3H, m), 8.30 (1H, dd, J˜8.0 Hz, 2.2 Hz), 9.23 (1H, d, J˜2.2Hz).

6-(3-Tert-butylphenylethynyl) nicotinic acid (Compound 2)

A solution of 60 mg (0.195 mmol) of ethyl 6-(3-tert-butylphenylethynyl)nicotinate (Compound 1) in 4 ml of aqueous ethanolic KOH was stirred atroom temperature for 24 hours. The mixture was concentrated in-vacuo andthe residue was treated with 5 ml of water and 5 ml of ether. Theaqueous layer was separated and washed with a further 5 ml of ether. Theaqueous layer was then acidified with 3 ml of 10 percent HCl andextracted with 2 x 5 ml of ether. The ether extracts were combined andwashed with saturated NaCl solution and then dried (MGSO₄). The solutionwas concentrated in-vacuo to give the title compound as a pale yellowsolid. PMR (CDCl₃): & 1.26 (9H, s), 7.25 (1H, t, J˜7.8 Hz), 7.35-7.42(2H, m), 7.56-7.63 (2H, m), 8.35 (1H, dd, J˜8.2 H, 2.1 Hz), 9.31 (1H, d,J˜2.1 Hz).

4-4-Bromophenyl-tert-butyl-sulfide (Compound 41)

A constant flow of isobutylene was bubbled through a solution of 4 g(21.16 mmol) of 4-bromo-thiophenol (Compound 40) in 250 ml of methylenechloride under a nitrogen atmosphere and the mixture treated slowly with0.6 ml of conc. H₂ SO₄. Isobutylene was bubbled through the reactionmixture at room temperature for 2.5 hours and the mixture then stirredfor a further 12 hours. The mixture was then washed successively withsaturated NaHCO₃, water, 1N HCl, water and saturated NaCl and then dried(MGSO₄) The solvent was then removed in-vacuo and the residue purifiedby flash chromatography (silica; 3% ethyl acetate in hexanes) to givethe title compound as a colorless oil. PMR (CDCl₃): & 1.28 (9H, s), 7.39(2H, d, J˜8.4 Hz), 7.47 (2H, d, J˜8.4 Hz).

3-Bromophenyl tert-butyl sulfide (Compound 55)

Isobutylene was bubbled through 75% H₂ SO₄ solution at-5 degrees C.until 2.65 g (47.2 mmol) of isobutylene had been absorbed. The mixturewas treated with 3.8 g (20.1 mmol) of 3-bromothiophenol and then allowedto warm to room temperature and stirred for 72 hours. The reactionmixture was then poured into 40 ml of an ice/water mixture and thenextracted with ether. The ether extracts were combined and washedsuccessively with 5% NaOH, water and saturated NaCl solution and thendried (MGSO₄) The solvent was removed in-vacuo and the residue distilled(69-75 degrees C., 0.6 mm) to give the title compound as a pale yellowoil. PMR (CDCl₃) & 1.30 (9H, s), 7.23 (1H, t, J˜8.0 Hz), 7.45-7.54 (2H,m), 7.72 (1H, t, J˜1.8 Hz). 4-Bromophenyl 3-methyl-2-butenyl sulfide(Compound 46)

A mixture of 12.8 g (67.7 mmol) of 4-bromothiophenol (Compound 4o) and2.7 g (67.7 mmol) of sodium hydroxide in 50 ml acetone was heated atreflux under argon for 2.5 hours. The refluxing mixture was then treateddropwise with a solution of 10.0 g (67.1 mmol) of4-bromo-2-methyl-2-butene (Compound 45) in 10 ml acetone and the mixtureheated at reflux for a further 24 hours. The mixture was then cooled andsolvent removed in-vacuo. The residue was treated with 50 ml water andextracted with 3×75 ml ether. The ether extracts were combined andwashed successively with 3×30 ml of 5% NaOH, 50 ml of water and 50 ml ofsaturated NaCl and then dried (MGSO₄). Solvent was then removed in-vacuoand the residual oil purified by kugelrohr distillation (70 degrees C.,0.1 mm) to give the title compound as a colourless oil. PMR (CDCl₃ ) &1.58 (3H, s), 1.70 (3H, s) 3.5 (2H, d, J˜7.0 Hz), 5.27 (1H, t, J˜7.0Hz), 7.17 (2H, d, J˜8.3 Hz), 7.36 (2H, d, J˜8.3 Hz).

4-Bromophenyl 3-methylbutyl sulfide (Compound 50)

A mixture of 15 g (79 mmol) of 4-bromo-thiophenol (Compound 40), 3.16 g(79 mmol) of powdered sodium hydroxide and 150 ml of acetone was heatedat reflux for 15 minutes. The refluxing mixture was then treateddropwise with a solution of 12 g (79 mmol) of 1-bromo-3-methylbutane(Compound 49) in 25 ml of acetone and then refluxed for a further 18hours. The mixture was allowed to cool and the solvent removed in-vacuo.The residue was taken up in 25 ml of water and the mixture basified with2N NaOH solution. The mixture was extracted with ether and the combinedether extracts washed successively with 1N NaOH, water and saturatedNaCl and then dried (MGSO₄). The solvent was removed in-vacuo and theresidue distilled (113-117 degrees C., 0.2 mm) to give the titlecompound as a colourless oil. PMR (CDCl₃): & 0.93 (6H, d, J˜6.6 Hz),1.47-1.58 (2H, m), 1.65-1.80 (1H, m), 2.90 (2H, t, J˜7.8 Hz), 7.18 (2H,d, J˜8.6 Hz), 7.39 (2H, d, J˜8.6 Hz).

Trimethylsilyl (4-thio-tert-butoxyphenyl) ethyne (Compound 42)

A mixture of 1.25 g (5.1 mmol) of 4-bromophenyl tert-butyl sulfide(Compound 41), 500 mg (5.1 mmol) of trimethylsilyl acetylene (Compound16), 100 mg (0.53 mmol) of cuprous iodide, 200 mg (0.28 mmol) of bis(triphenylphosphine) palladium (II) chloride and 1 ml of triethylaminewas degassed and then heated under argon at 55 degrees C. for 160 hours.The triethylamine was then removed under vacuum and the residue purifiedby flash chromatography (silica; hexanes) to give the title compound asa colourless oil. PMR (CDCl₃): & 0.20 (9H, s), 1.22 (9H, s), 7.32-7.42(4H, AB quartet).

Trimethylsilyl (3-thio-tert-butoxyphenyl) ethyne (Compound 56)

Using the same general procedure as described for Compound 42, but usinginstead 3-bromophenyl tert-butyl sulfide (Compound 55), the titlecompound was synthesized as a pale yellow oil. PMR (CDCl₃): & 0.25 (9H,s), 1.25 (9H, s), 7.22 (1H, t, J˜8.0 Hz), 7.39-7.46 (2H, m), 7.62 (1H,s).

Trimethylsilyl [4-(3-methyl-thio-2-butenoxy) phenyl] ethyne (Compound47)

Using the same general procedure as described for Compound 42, but usinginstead 4-bromophenyl 3-methyl-2-butenyl sulfide (Compound 46), thetitle compound was synthesized as a pale yellow oil. PMR (CDCl₃): & 0.25(9H, s), 1.62 (3H, s), 1.71 (3H, s), 3.55 (2H, d, J˜7.5 Hz), 5.28 (1H,t, J˜7.5 Hz), 7.21 (2H, d, J˜8.1 Hz), 7.36 (2H, d, J˜8.1 Hz).

Trimethylsilyl [4-(3-methyl-thiobutoxy) phenyl] ethyne (Compound 51)

Using the same general procedure, as described for Compound 42, butusing instead 4-bromophenyl 3-methyl-butyl sulfide (Compound 50), thetitle compound was synthesized as a colourless oil. PMR (CDCl₃): & 0.25(9H, s), 0.92 (6H, d, J˜ 6.6 Hz), 1.48-1.58 (2H, m), 1.65-1.79 (1H, m),2.92 (2H, t, J˜7.8 Hz), 7.20 (2H, d, J˜8.4 Hz), 7.37 (2H, d, J˜8.4 Hz).

4-Thio-tert-butoxyphenyl ethyne (Compound 39)

To a solution of 850 mg (3.24 mmol) of trimethylsilyl4-thio-tert-butoxyphenylethyne (Compound 42) in 3 ml of isopropanol wasadded 5 ml of 1N KOH solution and the mixture was stirred at roomtemperature for 16 hours. The mixture was extracted with ether and thecombined ether extracts were washed successively with dilute HCl, water,saturated NaHCO₃ and NaCl solutions and then dried (MGSO₄). The solventwas removed in-vacuo to give the title compound as a pale yellow oil.PMR (CDCl₃): & 1.29 (9H, s), 3.16 (1H, s), 7.42-7.52 (4H, AB quartet).

3-Thio-tert-butoxyphenyl ethyne (Compound 43)

Using the same general procedure as described for Compound 39, but usinginstead trimethylsilyl 3-thio-tert-butoxyphenyl ethyne (Compound 56),the title compound was synthesized as a colorless oil. PMR (CDCl₃): &1.30 (9H, s), 3.11 (1H, s), 7.31 (1H, t, J˜7.7 Hz), 7.48-7.56 (2H,m),7.69 (1H, t, J˜1.7 Hz).

4-(3-Methyl-thio-2-butenoxy) phenyl ethyne (Compound 44)

Using the same general procedure as described for Compound 39), butusing instead trimethylsilyl 4-(3-methyl-thio-2-butenoxy) phenyl ethyne(Compound 47), the title compound was synthesized as a pale yellow oil.PMR (CDCl₃): & 1.63 (3H, s), 1.72 (3H, s), 3.08 (1H, s), 3.56 (2H, d,J˜7.5 Hz), 5.29 (1H, t, J˜7.5 Hz), 7.23 (2H, d, J˜8.4 Hz), 7.38 (2H, d,J˜8.4 Hz).

4-(3-methyl-thiobutoxy) phenyl ethyne (Compound 48)

Using the same general procedure as described for Compound 39, but usinginstead trimethylsilyl 4-(3-methyl-thiobutoxy) phenyl ethyne (Compound51) the title compound was synthesized as a colourless oil. PMR (CDCl₃)& 0.93 (6H, d, J˜6.7 Hz), 1.49-1.60 (2H, m), 1.65-1.80 (1H, m), 2.93(2H, t, J˜7.8 Hz), 7.22 (2H, d, J˜8.5 Hz), 7.39 (2H, d, J˜8.5 Hz).

Ethyl 6-(3-thio-tert-butoxyphenyl) ethynyl nicotinate (Compound 7)

A mixture of 198 mg (1.04 mmol) of 3-thio-tert-butoxyphenyl ethyne(Compound 43), 193 mg (1.04 mmol) of ethyl 6-chloro-nicotinate (Compound54), 10 mg (0.05 mmol) of cuprous iodide, 20 mg (0.03 mmol) of bis(triphenylphosphine) palladium (II) chloride and 0.5 ml of triethylaminewas degassed under nitrogen and heated at 55-60 degrees C. for 40 hours.The triethylamine was removed under vacuum and the residue purified byflash chromatography (silica, 10% ethyl acetate in hexanes) to give thetitle compound as a pale brown solid. PMR (CDCl₃): & 1.31 (9H, s), 1.43(3H, t, J˜7.2 Hz), 4.43 (2H, q, J˜7.2 Hz), 7.36 (1H, t, J˜7.8 Hz), 7.55-7.66 (3H, m), 7.81 (1H, t, J˜1.7 Hz), 8.31 (1H, dd, J˜8.2 Hz, 2.2 Hz),9.22 (1H, d, J˜2.2 Hz).

Ethyl 6-(4-thio-tert-butoxyphenyl) ethynyl nicotinate (Compound 9)

Using the same general procedure as described for Compound 7, but usinginstead 4-thio-tert-butoxyphenyl ethyne (Compound 39), the titlecompound was synthesized as a pale brown solid. PMR (CDCl₃): & 1.31 (9H,s), 1.43 (3H, t, J˜7.1 Hz), 4.43 (2H, q, J˜7.1 Hz), 7.51-7.63 (5H, m),8.30 (1H, dd, J˜8.1 Hz, 2.1 Hz), 9.22 (1H, d, J˜2.1 Hz).

Ethyl 6-4-(3-methyl-thiobutoxy) phenyl] ethynyl nicotinate (Compound 57)

Using the same general procedure as described for Compound 7, but usinginstead 4-(3-methyl-thiobutoxy) phenyl ethyne (Compound 48), the titlecompound was synthesized as a brown solid. PMR (CDCl₃): & 0.93 (6H, d,J˜6.5 Hz) 1.42 (3H, t, J˜7.1 Hz), 1.53-1.62 (2H, m), 1.67-1.82 (1H, m),2.93-3.00 (2H, m)., 7.26 (2H, d, J˜8.4 Hz), 7.52 (2H, d, J˜8.4 Hz), 7.58(1H, d, J˜8.2 Hz) 8.29 (1H, dd, J˜8.2 Hz, Hz), 9.20 (1H, d, J˜2.1 Hz).

Ethyl-6-F4-(3-methyl-thio-2-butenoxy) phenyl] ethynyl nicotinate(Compound 11)

Using the same general procedure as described for Compound 7, but usinginstead 4-(3-methyl-thio-2-butenoxy) phenyl ethyne (Compound 44), thetitle compound was synthesized as a pale yellow solid. PMR (CDCl₃): &1.43 (3H, J˜7.1 Hz), 1.66 (3H, s), 1.74 (3H, s), 3.59 (2H, d, J˜7.5 Hz),4.43 (2H, q, J˜7.1 Hz), 5.31 (1H, t, J˜7.5 Hz), 7.28 (2H, d, J˜8.4 Hz),7.51 (2H, d, J˜8.4 Hz), 7.58 (1H, d, J˜8.1 Hz), 8.28 (1H, dd, J˜8.1 Hz,1,8 Hz), 9.20 (1H, d, J˜1.8 Hz).

6-4-(3-methyl-thio-2-butenoxy) phenyl] ethynyl nicotinic acid (Compound12)

Using the same general procedure as for Compound 2 but using insteadethyl 6-[4-(3-methyl-thio-2-butenoxy) phenyl] ethynyl nicotinate(Compound 11), the title compound was prepared as a pale yellow solid.PMR (CDCl₃): & 1.67 (3H, s), 1.75 (3H, s), 3.61 (2H, d, J˜7.5 Hz), 5.32(1H, t, J˜7.5 Hz), 7.30 (2H, d, J˜8.4 Hz), 7.53 (2H, d, J˜8.4 Hz), 7.61(1H, d, J˜8.7 Hz), 8.32 (1H, dd, J˜8.7 Hz, 2.1 Hz), 9.23 (1H, d, J˜2.1Hz).

Using the method described for the preparation of ethyl 6-(4-tertbutylphenyl)-ethynyl nicotinate (Compound 3), but using other examplesof reagents corresponding to General Formula 2 and General Formula 3,respectively, numerous specific examples of compounds of the inventioncan be prepared. Still further, as examples, the ethyne compounds(General Formula 2) which were specifically described above, i.e.

4-tert-butylphenyl ethyne (Compound 19);

3-tert-butylphenyl ethyne (Compound 22);

4-(4-methylpentyl)-phenylethyne (Compound 26);

4-(1,1,4-trimethylpentyl)phenylethyne (Compound 32);

4-thio-tert-butoxyphenyl ethyne (Compound 39);

3-thio-tert-butoxyphenyl ethyne (Compound 43)

4-(3-methyl-thio-2-butenoxy)phenyl ethyne (Compound 44);

4-(3-methyl-thiobutoxy)-phenyl ethyne (Compound 48)

can be coupled with the reagents (General Formula 3) noted above, i.e.with

ethyl 2-(2-chloropyrid-5-yl)acetate;

ethyl 5-(2-chloropyrid-5-yl)pentanoate;

ethyl 2-(2-iodofur-5-yl)acetate;

ethyl 5-(2-iodofur-5-yl)pentanoate;

ethyl 2-(2-iodothien-5-yl)acetate;

ethyl 5-(2-iodothien-5-yl)pentanoate;

ethyl 2-(3-chloropyridazin-6-yl)acetate;

ethyl 5-(3-chloropyridazin-6-yl)pentanoate

to provide a large number of further examples of compounds of theinvention.

EXAMPLES OF FORMULATION FOR TOPICAL ADMINISTRATION

Preferably the compounds of the invention may be administered topicallyusing various formulations. Such formulations may be as follows:

    ______________________________________                                        Ingredient          Weight/Percent                                            ______________________________________                                        Solution                                                                      Retinoid (active ingredient)                                                                      0.1                                                       BHT                 0.1                                                       Alcohol USP         58.0                                                      Polyesthylene Glycol 400 NF                                                                       41.8                                                      Gel                                                                           Retinoid (active ingredient)                                                                      0.1                                                       BHT                 0.1                                                       Alcohol USP         97.8                                                      Hydroxypropyl Cellulose                                                                           2.0                                                       ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR16## wherein R₁-R₃ independently are hydrogen, lower alkyl, lower cycloalkyl or loweralkenyl, A and B independently are hydrogen, lower alkyl, lowercycloalkyl, lower alkenyl, SR₄ or OR₄ where R₄ is lower alkyl, lowercycloalkyl or lower alkenyl;Y is furyl; E is divalent lower alkenyl,lower alkynyl, lower cycloalkyl, lower branched chain alkyl, or ischaracterized by the formula (CH₂)_(n) where n is 0-5, and Z is OH, OR₅,OCOR₅, --COOH or a pharmaceutically acceptable sale, ester or amidethereof, --CHO, CH(OR₇)₂ CHOR₈ O, or COR₉ or CR₉ (OR₇)₂, CR₉ OR₈ o,where R₅ is lower alkyl, phenyl or lower alkylphenyl, R₇ is lower alkyl,R₈ is a divalent alkyl radical of 2-5 carbons, and R₉ is an alkyl,cycloalkyl or alkenyl group having 1 to 5 carbons.
 2. A compound ofclaim 1 wherein A and B independently are hydrogen, lower alkyl,cycloalkyl, or lower alkenyl.
 3. A compound of claim 2 wherein one ofthe A and B groups is lower alkyl.
 4. A compound of claim 3 wherein R₁-R₃ all are hydrogen.
 5. A compound of claim 2 wherein E ischaracterized by the formula (CH₂)_(n), where n is 0-5.
 6. A compound ofclaim 2 wherein Z is --COOH or a pharmaceutically acceptable salt, esteror amide thereof.
 7. A compound of claim 6 wherein Z is a carboxylicacid ester.
 8. A compound of claim 1 wherein one of the A and B groupsis SR₄ where R₄ is lower alkyl, lower cycloalkyl or lower alkenyl.
 9. Acompound of claim 8 wherein R₁ -R₃ all are hydrogen.
 10. A compound ofclaim 8 wherein E is characterized by the formula (CH₂)_(n) where n is0-5.
 11. A compound of claim 8 wherein Z is --COOH or a pharmaceuticallyacceptable salt, ester or amide thereof.
 12. A compound of claim 11wherein Z is carboxylic acid ester.
 13. A compound of claim 2 wherein Yrepresents a furan ring.
 14. A compound of claim 1 where Y is furylsubstituted with the E-Z group.
 15. A compound of claim 14 where Y isfuryl substituted in the 2 and 5 positions.
 16. A pharmaceuticalcomposition comprising an effective amount of a compound set forth inclaim 1, in combination with a pharmaceutically acceptable excipient,the composition being used for treating dermatoses, epithelial cancers,arthritic diseases, immunological disorders, for promoting woundhealing, treating dry eye syndrome, for delaying sun damage andreversing the effects of sun damage to skin, the composition containingthe compound of claim 1 in the range of 0.001 to 5 percent by weight.